Hypertrophy of the cardiac myocyte is an important adaptive response of the heart to many hemodynamic stresses, such as hypertension, valvular heart disease, and the loss of myocytes associated with myocardial infarction or cardiomyopathy. Although mirrored by processes in cultured cells, and extracellular matrix. Putative growth factors and their signaling pathways may be evaluated in vitro, but the gold standard will remain cardiac hypertrophy in the intact animal. Transgenic mice offer the opportunity to genetically target expression of growth factors and intracellular signaling molecules directly to all the cardiac myocyte of animals. Recently developed techniques allow the assessment of in vivo cardiac function in the mouse. Accordingly, the long term goal of this project is to target expression of putative growth factors and components of intracellular signaling cascades to the cardiac myocyte in vivo, and to assess the effect alterations on cardiac morphology, function, and gene expression. The feasibility of this approach is demonstrated by the recent generation of transgenic mice expressing oncogenic H-ras in the heart, with an increase in left ventricular mass. We thus propose the following Specific Aims: 1) To determine whether expression of a constitutively activated ras mutant is sufficient for the induction of cardiac myocyte hypertrophy in vivo: 2) To determine whether a constitutively activated ras mutant is additive to other hypertrophic stimuli in producing in vivo hypertrophy; 3) TO determine whether activated ras can complement the decrease in heart size seen in IGF-1 deficient transgenic mice; 4) To determine whether ras is necessary for the induction of cardiac myocyte hypertrophy in vivo, by expressing a dominant interfering ras mutant in the transgenic mouse heart. The result of these studies should define the role of the p21 ras molecular "switch" in the genesis of myocyte hypertrophy, and provide a paradigm for future characterization of other signaling pathways.